The crizotinibresistant ALKF1174L mutation arises de novo in neuroblastoma (NB) and is acquired in ALK translocation-driven cancers, lending impetus to the development of novel ALK inhibitors with different modes of action. The diaminopyrimidine TAE684 and its derivative ceritinib (LDK378), which are structurally distinct from crizotinib, are active against NB cells expressing ALKF1174L. Here we demonstrate acquired resistance to TAE684 and LDK378 in ALKF1174L-driven human NB cells that is linked to overexpression and activation of the AXL tyrosine kinase and epithelial-to-mesenchymal transition (EMT). AXL phosphorylation conferred TAE684 resistance to NB cells through upregulated ERK signaling. Inhibition of AXL partly rescued TAE684 resistance, resensitizing these cells to this compound. AXL activation in resistant cells was mediated through increased expression of the active form of its ligand, GAS6, which also served to stabilize the AXL protein. Although ectopic expression of AXL and TWIST2 individually in TAE684-sensitive parental cells led to the elevated expression of mesenchymal markers and invasive capacity, only AXL overexpression induced resistance to TAE684 as well. TAE684-resistant cells showed greater sensitivity to HSP90 inhibition than did their parental counterparts, with downregulation of AXL and AXL-mediated ERK signaling. Our studies indicate that aberrant AXL signaling and development of an EMT phenotype underlie resistance of ALKF1174L-driven NB cells to TAE684 and its derivatives. We suggest that the combination of ALK and AXL or HSP90 inhibitors be considered to delay the emergence of such resistance.
ALK inhibitor resistance in ALK(F1174L)-driven neuroblastoma is associated with AXL activation and induction of EMT.
Specimen part, Cell line
View SamplesWe conducted microarray experiments by comparing constitutive and inducible Flowering Locus T1 (FT1) and FT2 constructs with appropriate controls, followed by the identification of common targets of Pro35S:FT1 and ProHSP:FT1 or Pro35S:FT2 and ProHSP:FT2.
FLOWERING LOCUS T duplication coordinates reproductive and vegetative growth in perennial poplar.
Specimen part, Treatment
View SamplesThe aim of the study was to get insights into transcriptional alterations in bone marrow mesenchymal stromal cells derived from acute myeloid leukemia patients
Molecular alterations in bone marrow mesenchymal stromal cells derived from acute myeloid leukemia patients.
Disease
View SamplesGenome-wide gene expression analysis on tibialis anterior muscle from 2-month-old nebulin SH3 domain deleted (NebSH3) mice compared to wildtype.
The nebulin SH3 domain is dispensable for normal skeletal muscle structure but is required for effective active load bearing in mouse.
Sex, Age, Specimen part
View SamplesGene expression from primary neuronal, astrocytic, oligodendrocytic and microglial cultures, as well as from RNA mixtures thereof.
Population-specific expression analysis (PSEA) reveals molecular changes in diseased brain.
Specimen part
View SamplesIn this study the gene expression in cells infected with lytic and non-lytic variants of coxsackievirus B2 Ohio (CVB2O) were analyzed using next generation sequencing. This approach was selected with the purpose of elucidating the effects of lytic and non-lytic viruses on host cell transcription. Total RNA was extracted from infected cells, next generation sequencing was performed, and the reads were subsequently mapped against the human and CVB2O genomes. The amount of intracellular virions was measured, showing a relative amount of virus RNA 13 times higher in the cells infected with the lytic variant, vVP1Q164K, compared to cells infected by the non-lytic CVB2Owt. Furthermore, differential gene expression in the cells infected with the two viruses was identified and a number of genes singled out as possible keys to the answer of how the viruses interact with the host cells, resulting in lytic or non-lytic infections. Overall design: 4 samples, two samples of one strain, one sample of a different strain, and one control sample
The Transcriptome of Rhabdomyosarcoma Cells Infected with Cytolytic and Non-Cytolytic Variants of Coxsackievirus B2 Ohio-1.
No sample metadata fields
View SamplesIL-2 production defines precursors fated to become T Follicular Helper cells Overall design: Sorted naïve IL-2.eGFP CD4 T cells were activvated in vitro or in vivo. Total RNA was isolated from CD69+ IL-2.eGFP+ and CD69+ IL-2.eGFP– CD4 T cells 18-24 hours after activation.
Differential IL-2 expression defines developmental fates of follicular versus nonfollicular helper T cells.
Specimen part, Cell line, Subject
View SamplesGene expression profiling of the medial (MGE), lateral (LGE) and caudal (CGE) ganglionic eminence, and cerebral cortex (CTX) at various embryonic stages (E12.5, E14 and E16).
Comprehensive spatiotemporal transcriptomic analyses of the ganglionic eminences demonstrate the uniqueness of its caudal subdivision.
Sex, Specimen part
View SamplesTo identify gene expression changes associated with Crtc1 deficiency, we performed genome-wide transcriptome profile analyses by using mouse cDNA microarrays in the cortex of Crtc1/ and WT female mice
Involvement of the agmatinergic system in the depressive-like phenotype of the Crtc1 knockout mouse model of depression.
Sex, Specimen part
View SamplesEmerging evidence suggest that miRNAs play an essential role in self-renewal and differentiation of normal and malignant stem cells by regulating the expression of key stem cell regulatory genes. Here we demonstrate that mir-100 expression is related to cellular differentiation state with lowest expression in cells displaying stem cell markers. Utilizing a tetracycline inducible lentivirus driving mir-100 expression, we found that mir-100 overexpression decreased breast cancer stem cells (BCSCs) and inhibited cancer cell proliferation in vitro and in mouse xenografts by targeting SMARCA5, SMARCD1 and BMPR2.
MicroRNA100 inhibits self-renewal of breast cancer stem-like cells and breast tumor development.
Cell line, Treatment
View Samples